Unlaid Eggs: Ovarian Damage after Low-Dose Radiation

Abstract

The total body irradiation of lymphomas and co-irradiation in the treatment of adjacent solid tumors can lead to a reduced ovarian function, premature ovarian insufficiency, and menopause. A small number of studies has assessed the radiation-induced damage of primordial follicles in animal models and humans. Studies are emerging that evaluate radiation-induced damage to the surrounding ovarian tissue including stromal and immune cells. We reviewed basic laboratory work to assess the current state of knowledge and to establish an experimental setting for further studies in animals and humans. The experimental approaches were mostly performed using mouse models. Most studies relied on single doses as high as 1 Gy, which is considered to cause severe damage to the ovary. Changes in the ovarian reserve were related to the primordial follicle count, providing reproducible evidence that radiation with 1 Gy leads to a significant depletion. Radiation with 0.1 Gy mostly did not show an effect on the primordial follicles. Fewer data exist on the effects of radiation on the ovarian microenvironment including theca-interstitial, immune, endothelial, and smooth muscle cells. We concluded that a mouse model would provide the most reliable model to study the effects of low-dose radiation. Furthermore, both immunohistochemistry and fluorescence-activated cell sorting (FACS) analyses were valuable to analyze not only the germ cells but also the ovarian microenvironment.

Radiotherapy, Female Fertility and Ootoxicity

“…Not enough information exists about the effect of relatively low-dose exposures in the long term (5,23). In the preclinical study of Reiser et al, 0.1 Gy was applied to the ovary, and this dose had no significant effect on primordial follicles (23). Similarly, in the study of Kimler et al, no change was observed in ovarian follicles with 0.1 Gy, whereas a significant decrease was observed at 1 Gy in a mouse model (35).…”

“…The most common type of follicle in the human ovary is the primordial follicle, which represents the ovarian reserve. This reserve reaches the maximum level in the intrauterine 5th month in the fetus, then ovarian functions gradually decrease with age, and the menstrual cycle ends by completely losing its activities at an average age of 50-52 years (23). Although a natural decrease occurs in the number of oocytes between birth and menopause, RT can accelerate this, resulting in early menopause and infertility (15).…”

“…In addition to germ cells, the ovaries contain somatic cells, and these also contribute to the quality and quantity of germ cells. Somatic cells make up the majority of the ovarian cortex and are distributed as follows: stromal cells (83%); oocytes (0.2%); perivascular cells (10%); endothelial cells (5%); granulosa (1.2%); theca and immune cells (0.4%) (23). The fact that these non-oocyte cells undergo apoptosis and necrosis within hours after radiation shows that they are also radiosensitive.…”

“…Doses predicted to cause damage in preclinical studies were administe-red over a short time. Not enough information exists about the effect of relatively low-dose exposures in the long term (5,23). In the preclinical study of Reiser et al, 0.1 Gy was applied to the ovary, and this dose had no significant effect on primordial follicles (23).…”

Impact of ovary-sparing treatment planning on plan quality, treatment time and gamma passing rates in intensity-modulated radiotherapy for stage I/II cervical cancer

“…[ 4 , 5 ] In order to achieve the goal of ovary-sparing in radiotherapy, the ovaries need to be consciously transposed during surgery, away from the area of anticipated irradiation to lower the exposure dose. [ 6 , 7 ] Hwang et al [ 8 ] counted 53 patients with cervical cancer who underwent ovarian transposition. By analyzing the patients’ symptoms and serum follicle-stimulating hormone (FSH) level, they found that the position of the transposed ovary (odds ratio 11.72, 95% conformity index [CI] 1.64–83.39) was the most important factor influencing the ovary-sparing.…”